Therapeutic efficacy of ECs Foxp1 targeting Hif1α-Hk2 glycolysis signal to restrict angiogenesis
Jingjiang Pi,
Jie Liu,
Huan Chang,
Xiaoli Chen,
Wenqi Pan,
Qi Zhang,
Tao Zhuang,
Jiwen Liu,
Haikun Wang,
Brian Tomlinson,
Paul Chan,
Yu Cheng,
Zuoren Yu,
Lin Zhang,
Zhenlin Zhao,
Zhongmin Liu,
Jie Liu,
Yuzhen Zhang
Affiliations
Jingjiang Pi
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Shenzhen Ruipuxun Academy for Stem Cell and Regenerative Medicine, Shenzhen, China; Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Jie Liu
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Huan Chang
Department of Electrophysiology, Jingjiang People's Hospital Affiliated to Yangzhou University, Yangzhou, 225000, China
Xiaoli Chen
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Wenqi Pan
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Qi Zhang
Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Tao Zhuang
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
Jiwen Liu
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Haikun Wang
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, University of Chinese Academy of Sciences, 320 Yueyang Rd, Shanghai, 200031, China
Brian Tomlinson
Faculty of Medicine, Macau University of Science and Technology, Macau SAR, China
Paul Chan
Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Yu Cheng
Institute for Biomedical Engineering and Nano Science, Tongji University School of Medicine, Shanghai, China
Zuoren Yu
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Lin Zhang
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
Zhenlin Zhao
Shenzhen Ruipuxun Academy for Stem Cell and Regenerative Medicine, Shenzhen, China; Corresponding authors.
Zhongmin Liu
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Corresponding author. Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai, 200120, China.
Jie Liu
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Shenzhen Ruipuxun Academy for Stem Cell and Regenerative Medicine, Shenzhen, China; Corresponding authors. Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai, 200120, China.
Yuzhen Zhang
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai Heart Failure Research Center, Department of Cardiology, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China; Corresponding author. Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai, 200120, China.
Endothelial cells (ECs) rely on glycolysis for energy production to maintain vascular homeostasis and the normalization of hyperglycolysis in tumor vessels has recently gained attention as a therapeutic target. We analyzed the TCGA database and found reduced Foxp1 expression in lung carcinoma. Immunostaining demonstrated reduced expression more restricted at tumor vascular ECs. Therefore, we investigated the function and mechanisms of Foxp1 in EC metabolism for tumor angiogenesis required for tumor growth. EC-Foxp1 deletion mice exhibited a significant increase of tumor and retinal developmental angiogenesis and Hif1α was identified as Foxp1 target gene, and Hk2 as Hif1α target gene. The Foxp1-Hif1α-Hk2 pathway in ECs is important in the regulation of glycolytic metabolism to govern tumor angiogenesis. Finally, we used genetic deletion of EC-Hif1α and RGD-peptide nanoparticles EC target delivery of Hif1α/Hk2-siRNAs to knockdown gene expression which reduced the tumor EC hyperglycolysis state and restricted angiogenesis for tumor growth. This study advances our understanding of EC metabolism for tumor angiogenesis, and meanwhile provides evidence for future therapeutic intervention of hyperglycolysis in tumor ECs for suppression of tumor growth.
